Compared to development of new drugs, drug delivery products often demand less development time and costs, especially when the active ingredient has been previously well characterized for safety and toxicity. In addition, drug delivery technologies can be used for new chemical entities (NCE), enabling them to be formulated in spite of challenging pharmaceutical properties. (M. V. Chaubal, “Application of Drug Delivery Technologies in Lead Candidate Selection and Optimization”, Drug Discovery Today, 9, (14), 603-609, 2004).
Controlled release and targeted delivery of drugs are two major concepts the drug delivery technologies are based on. Successful realization of these concepts can reduce side effects, improve bioavailability and stability of many drugs as well as enhance patient compliance and prevent medication errors.
The oral route is the most convenient method of drug administration and even small improvements in oral drug delivery technology may enhance patient compliance and drug bioavailability. The current drug delivery technologies are mainly focused on delayed release, i.e., no release until the dosage form reaches the specific region of GIT such as upper intestine or colon. For example, site specific delivery into the upper intestine has been achieved for many years by the use of pH-sensitive coatings.
Gelatin capsules are most popular for oral drug delivery, but the physicochemical properties of the gelatin capsule shell present significant challenges when these capsules are being coated with enteric polymers. HPMC capsules have some advantages compared to gelatin ones and U.S. Pat. No. 7,094,425 provides HPMC capsule with a suitable coating such that the drug is released from the capsule either in the small intestine or the colon.
However, there still remains an urgent need for new materials allowing further progress in the area
Injectable in situ forming devices (ISFDs) based on biodegradable biocompatible polymers are very attractive as controlled release drug delivery systems. They are potentially compatible with all types of tissues and drugs, offer systemic or local drug delivery, easy to administer, simple and inexpensive to produce.
Similar to injectable drug delivery systems based on microspheres, ISFDs avoid the incision needed to implant drug delivery systems. However, the manufacture and storage of microspheres present a lot of problems. Also, once implanted in the body, due to their particulate nature, the microspheres tend to aggregate and migrate, which makes their behaviour hard to predict. Further, if there are some complications, removal of microspheres from the body without extensive surgical intervention is considerably more difficult or impossible.
At present, proteins and peptides are becoming common drugs and a lot of recombinant proteins are in clinical trials or have already received approval of regulatory authorities. In current treatments, frequent injections or infusion therapy are the prescribed dosing regimes for most of them and due to the short plasma half-life and instability of proteins, there are urgent needs for suitable delivery systems. ISFDs are theoretically excellent delivery systems for such type of drugs.
Despite intense efforts aimed at developing the technology in order to avoid the problem of protein instability during the production of ISFD, progress within this field has been very slow, the main reason probably being that the three-dimensional structure for the majority of proteins is far too sensitive to withstand the manufacturing conditions used. For example, the scientific literature contains numerous descriptions of stability problems in the manufacture of implants based on degrading poly(lactic-co-glycolic acid) (PLGA) owing to exposure to organic solvents and the acidic environment which is formed upon the degradation of PLGA matrices. It has recently been shown that the pH value in a PLGA microsphere falls to 1.5, which is fully sufficient to denature or damage many therapeutically usable proteins (Fu et al, Visual Evidence of Acidic Environment Within Degrading Poly(lactic-co-glycolic acid) (PLGA) Microspheres, Pharmaceutical Research, Vol. 17, No. 1, 2000, 100-106). For PLGA implants the pH value can be expected to fall further owing to the fact that the acidic degradation products then get more hindered from diffusing away and the autocatalytic reaction of degradation is intensified. The nature of PLGA biodegradation is such that the degradation products formed are able to catalyze further hydrolysis, by virtue of their acid groups, and this leads to an intensive biodegradation and high rate of biodegradation, and consequently a substantial reduction of the pH inside the microparticles, some weeks, or months, after injection of the formulation.
A number of attempts to solve the above-described problems caused by exposure of the biologically active substance to a chemically acidic environment during the biodegradation of the PLGA matrix and organic solvents in the manufacturing process have been described. Attempts have been made to replace PLGA as the matrix by polymers that produce chemically neutral degradation products, e.g., amino acids and PEG (US Patent Application 20040077780).
Some excellent reviews on ISFD are:
“New biodegradable polymers for injectable drug delivery systems” (B. Jeong, Y. K. Choi, Y. H. Bae, G. Zentner, S. W. Kim, Journal of Controlled Release 62 (1999) 109-114)
“In situ forming parenteral drug delivery systems: an overview” (C. B. Packhaeuser, J. Schnieders, C. G. Oster, T. Kissel, European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) 445-455),
“In situ-forming hydrogels—review of temperature-sensitive systems. Review article” (Eve Ruel-Gariepy, Jean-Christophe Leroux, European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) 409-426).
In situ gelation of injectable systems can be based on change in molecular association of specific polymers driven by changes in temperature, pH, ion or solvent composition. Many polymers, which can be potentially used for ISFD, are new chemical entities (NCE) and not suitable for parenteral administrations, especially repeated parenteral administration, for a number of reasons. The most important of all is low biocompatibility of polymer matrices with mammal's tissues.
From the above, it appears that there is an emerging need for biodegradable and biocompatible materials that gel in situ and that may be used in a process for the production of ISFD for controlled, sustained or delayed release of biologically active substances.
Such biodegradable and biocompatible materials should be such as to permit the biologically active substances to be entrapped under conditions which allow them to retain their biological activity, in a process which permits high loading of a parenterally administrable preparation even with sensitive, biologically active substances.
The biodegradable and biocompatible materials should also be such as to allow a substantially fully biodegradable and biocompatible preparation to be produced and applied.